American Journal of Hematology 78:232239 (2005)

Current Views in HTLV-I-Associated Adult T-Cell

Leukemia/Lymphoma
Christophe Nicot
Department of Microbiology, Immunology and Molecular Genetics, University of Kansas Medical Center, Kansas City, Kansas

Epidemiological studies have demonstrated that the relative percentage of malignant lymphoid proliferations varies widely according to geographical location and ethnic populations. HTLV-I is the etiological agent of adult T-cell leukemia/lymphoma (ATLL) and is also
associated with cutaneous T-cell lymphoma (CTCL). However, a definite role of HTLV-I in
mycosis fungoides (MF) and/or Sezary syndrome (SS) remains controversial. While most
HTLV-I-infected individuals remain asymptomatic carriers, 15% will develop ATLL, an invariably fatal expansion of virus-infected CD4+ T cells. This low incidence and the long latency
period preceding occurrence of the disease suggest that additional factors are involved in
development of ATLL. In this review, diagnosis, clinical features, and molecular pathogenesis of HTLV-I are discussed. Am. J. Hematol. 78:232239, 2005. 2005 Wiley-Liss, Inc.

DISCOVERY AND EPIDEMIOLOGY

In 1977, epidemiological studies revealed the presence of unusual clusters of adult T-cell leukemia/
lymphoma (ATLL) in some areas of Japan, suggesting
a transmissible agent may be involved in the disease [1].
The first description of HTLV-I came after the discovery of the human T-cell growth factor (interleukin-2;
IL-2) [2], allowing long-term in vitro culture of T cells
and establishment of T-cell lines from a patient with a
cutaneous T-cell lymphoma (CTCL) [3]. Soon after,
this virus was identified as the etiological agent of
ATLL [4], and the term HTLV-I was adopted.
The relative percentage of malignant lymphoid
proliferations varies widely according to geographical
location, probably reflecting exposure to different
etiological factors, including viruses. Peripheral T-cell
lymphoma (PTCL) is relatively uncommon in Caucasian populations. For patients with non-Hodgkin lymphoma (NHL), the proportion of PTCL is only around
10% in Western countries [5] while the incidence of
PTCL is as high as 70% in southwestern Japan, where
HTLV-I infection is endemic. A recent survey of
lymphoid malignancies in Japan showed that 50%
were B-cell lymphoma and 42% were T/natural killer
(NK)-cell lymphoma, among which 58% were HTLV-I
infected while only 4% were Hodgkin lymphoma
(HL) [6].
2005 Wiley-Liss, Inc.

All routes of HTLV-1 virus transmission require

close contact with infected T-lymphocytes. Motherto-child transmission is associated with prolonged
breast-feeding in the postnatal period [710] and has
been associated with an increased risk of developing
ATLL. HTLV-1 can be sexually transmitted with a
higher transmission efficiency from male to female
than from female to male [11,12]. The intravenous
route of infection, mainly by blood transfusion,
appears to be the most efficient mode for HTLV-1
transmission [13]. The intravenous route of contamination is associated with a higher risk of developing tropical spastic paraparesis/HTLV-1 associated
Contract grant sponsor: National Institutes of Health; Contract
grant number: RR016443 (NIH) from the COBRE Program of the
National Center for Research Resources; Contract grant sponsor:
Lied Basic Science Research Grant of the University of Kansas
Medical Center Research Institute.
*Correspondence to: C. Nicot, University of Kansas Medical
Center, Department of Microbiology, Immunology and
Molecular Genetics, 3025 Wahl Hall West, 3901 Rainbow
Boulevard, Kansas City, KS 66160. E-mail: cnicot@kumc.edu
Received for publication 28 May 2004; Accepted 29 September
2004
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/ajh.20307

Concise Review: Current Views in HTLV-I-Associated Adult T-Cell Leukemia/Lymphoma

myelopathy (TSP/HAM). Transmission of HTLV-I

by blood transfusion occurs with transfusion of cellular blood products (whole blood, red blood cells,
and platelets) but not with the plasma fraction or
plasma derivatives from HTLV-I-infected blood. Seroconversion rates of 4463% have been reported in
recipients of HTLV-I-infected cellular components in
HTLV-I endemic areas.
In 1988, the Food and Drug Administration (FDA)
recommended all blood donation centers screen the
U.S. blood supply for HTLV-I. In 2001, data relating
to all blood donations to the American Red Cross
indicated the rates per 100,000 were 9.7 for HIV and
9.6 for HTLV. Incidences of new infection among
donors were 1.554 and 0.239 for HIV and HTLV,
respectively. Current estimations indicate 2030 million people worldwide are infected with HTLV-I.
Endemic areas are mainly found in Japan, Africa,
South America, Caribbean basin, Southern parts of
North America, and Eastern Europe. While most
HTLV-I-infected individuals remain asymptomatic
carriers, 15% (lifelong risk) will develop ATLL, an
invariably fatal expansion of virus-infected CD4+
T cells. The human T-cell lymphotropic virus type II
(HTLV-II) resembles HTLV-I in provirus organization and exerts less lymphoproliferative effects on the
hosts infected cells. To date, a clear association of
HTLV-II with a specific human disease has not been
established.
DIAGNOSIS CRITERIA

The diagnosis of ATL is usually made on morphological analysis. Cytological examination may reveal
infiltration by cerebriform or flower cells (activated
lymphocytes with convoluted nuclei and basophilic
cytoplasm), indicators of acute or lymphoma type
ATL. This must be confirmed by clonal integration of
HTLV-I provirus in the host genome. The predominant
immunological phenotype of neoplastic cells is helper
T-cell, CD3+, CD4+, L-selectin+, CD25+, CD45RA+,
HLA-DR+, CD29 , and CD45RO in peripheral
blood, or CD3+, CD4+, L-selectin+, CD29+,
CD45RO+, HLA-DR+, and CD45RA in the skin
and lymph nodes [14,15]. Phenotypic as well as morphological heterogeneity of ATL cells and heterogeneity of CD45R isoform expression on ATL cells can be
found in different organs. The CD7 and CD8 antigens
are usually absent. Factors signifying a poor prognosis
include high serum thymidine kinase levels [16,17], high
serum soluble interleukin-2 receptor levels [18], high
serum b2-microglobulin levels [19], high expression
of the Ki67 antigen, and high serum parathyroid
hormone-related protein levels. The serum neuronspecific enolase (NSE) value positively correlated with

233

serum thymidine kinase activity and serum soluble

interleukin-2 receptor levels. Because ATL cells produce significantly more NSE than other NHL cells,
serum NSE may serve as a marker of disease aggressiveness as well as a prognostic factor for ATL [20].
Whether HTLV-1-associated malignancies are referred
to as leukemias or lymphomas depends on specific
criteria found in the peripheral blood. Acute ATL is
characterized by a massive infiltration of the peripheral
blood by ATL cells, while the ATL lymphoma is characterized by the presence of less than 1% of leukemic
cells on a blood smear and major involvement of lymphoid organs.
The T-cell receptor expressed on leukemic cells is
usually a heterodimer of a and b chains. There are no
reports showing that particular variable segments of
the b chain genes are preferentially expressed in the
leukemic cells of ATLL patients, indicating leukemic
cells are not derived from particular antigen-specific
T-cell clones. According to the Revised European
American Lymphoma (REAL) classification of nonHodgkin lymphomas (NHL), with emphasis on
immunophenotypic analysis along with clinical features, ATLL belongs to the category of peripheral
T-cell lymphoma (PTCL) and natural killer-cell neoplasms. Shirono et al. proposed that ATL is characterized as acute when more than 18% of PBMCs are
found to be Ki-67 antigen-positive [21].
No specific karyotypic abnormalities have been
associated with the development of ATLL, but cytogenetic analyses of leukemic cells revealed multiple
abnormalities such as trisomy 3, 7, and 21, involvement of chromosomes 6 and 14, and loss of chromosome Y [2225]. Recently, loss of heterozygosity on
chromosome 6q [region (6q1521)] was reported in
approximately 50% of acute/lymphoma ATL, suggesting the presence in this location of a putative
tumor-suppressor gene involved in ATLL pathogenesis [26]. The cytogenetic abnormalities found in
ATLL are more frequent in the acute and lymphoma
types than in the chronic or the smoldering types.
Whether or not these genetic alterations are the
cause or the result of ATL is unknown.
HTLV-I-Associated Cutaneous T-Cell Lymphoma
(CTCL)

ATLL prevalence is often underestimated due to the

severity and the rapid evolution of this disease, and the
confusion of ATLL with Sezary syndrome (SS), mycosis fungoides (MF), or other types of T-cell NHL.
There are marked similarities between the clinical and
histopathological features of the lymphoma type of
ATLL and other types of cutaneous T-cell lymphoma
(CTCL) including SS, MF, and CD30 anaplastic large

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Concise Review: Nicot

cell CTCL. Importantly, liver invasion by ATLL cells

and impaired hepatic functions are frequent in HTLVI-infected individuals as opposed to NHL that are not
associated with HTLV-I infection. Most patients with
CTCL are negative for antibodies to the structural
proteins of HTLV-I, and thus a causative role for this
virus is usually dismissed. However, numerous studies
have found HTLV-I-related proviral tax sequence or
deleted proviruses in tumor samples from CTCL
patients [2734]. Recently a study on the northeastern
coast of Brazil found HTLV-I integrated proviral
sequences by southern blot in several mycosis fungoides-like cutaneous lymphomas, and CD30+ largecell anaplastic lymphomas [35]. However, other studies
could not identify any HTLV-I sequences in MF or SS
patients, and therefore a causative role for HTLV-I
remains controversial [3640].
It is well accepted that HTLV-I is associated with a
cutaneous-lymphoma type of ATL, in which detection
of monoclonal integration of HTLV-I and T-cell
monoclonality can be detected in the skin, but usually
not in the peripheral lymphocytes of ATL patients
[4144]. Various cutaneous lesions have been described
in ATL lymphoma, including papules, nodules, erythroderma, plaques, tumors, and ulcerative lesions. The
frequent expression of the chemokine (C-C motif)
receptor 4 (CCR4) on the surface of tumor cells may
in part explain skin involvement [45,46]. Other factors
such as expression of cutaneous lymphocyte antigen
(CLA) [47,48], expression of lymphocyte chemoattractant chemokine, stromal cell-derived factor/pre-B-cell
growth-stimulating factor (SDF-1/PBSF) [45], as well
as inflammatory responses may lead to chemotaxis of
infected lymphocytes [49] and contribute to skin infiltration by ATL cells. Virus-infected cells can remain in
the skin for several months or years before their dissemination to the peripheral blood and organs.
Clinical Features of HTLV-I-Associated ATL
and ATL Lymphoma

In addition to ATLL, HTLV-I is also the etiological

agent of an inflammatory neurodegenerative disorder
called tropical spastic paraparesis/HTLV-I-associated
myelopathy (TSP/HAM), as well as HTLV-I-associated arthropathy (HAAP), HTLV-I-associated uveitis (HAU), infective dermatitis, and polymyositis. The
role of HTLV-I in TSP/HAM pathogenesis has
recently been reviewed [5052].
ATLL has a broad clinical spectrum divided into four
clinically distinct entities (acute, chronic, smoldering,
and lymphoma) that differ in their presentation, progression and response to treatment [53].
Acute ATLL is characterized by fever, cough, lymphoadenopathy, skin lesions, hepatosplenomegaly,

marked leukocytosis, and hypercalcemia frequently

associated with lytic bone lesions and generalized
bone resorbtion. About 70% of ATL patients develop
high serum calcium levels during the clinical course of
the disease, particularly during the aggressive stage
[54,55]. High serum levels of lactate dehydrogenase, a
soluble form of the interleukin-2 receptor a chain,
and atypical lymphocytes with characteristic convoluted or lobulated nuclei and basophilic cytoplasm,
are also characteristic of the acute type of ATL. The
mean survival time is 6 months with a poor response
to chemo- or radiotherapy.
Chronic-type ATL is characterized by milder clinical symptoms and signs and a longer clinical course.
Serum calcium levels are normal and there is no
organ involvement other than lymphadenopathy,
cutaneous or pulmonary lesions, and hepatosplenomegaly. Chronic lymphocytosis, with more than 10%
circulating leukemia cells and a tendency to be less
cytologically atypical than in the acute type, is also an
indicator of chronic type ATL. The mean survival
time is 24 months.
The smoldering type is characterized by few leukemia
cells in the peripheral blood (less than 5%) and may
present with skin lesions such as papules, nodules, and
erythema. Lymph node enlargement and splenomegaly
are minimal, and serum lactate dehydrogenase levels
are either slightly elevated or normal; hypercalcemia is
usually not detected. Survival is quite long. Both
chronic and smoldering types can progress into an
acute form of leukemia or lymphoma following a progressive aggravation of the clinical picture. Progression
appears to be linked with an increase from low to high
proviral loads, possibly through exposure to chronic
antigen stimulation.
Lymphoma type ATLL is predominantly characterized by lymph node enlargement without manifestations of leukemia. Peripheral blood lacks absolute
lymphocytosis, but sporadic circulating leukemia cells
may be seen (<1%); hypercalcemia is absent. Mean
survival time for this group of patients is 10 months,
and response to chemotherapy is generally poor. The
4-year survival rates are 5.0% for the acute type,
5.7% for the lymphoma type, 26.9% for the chronic
type, and 62.8% for the smoldering type.
A major complication of ATLL is the immunodeficiency of patients that leads to serious infections with
bacteria, fungi, protozoa, and viruses. Common infections include Pneumocystis carinii, aspergillosis, candidiasis, cytomegalovirus pneumonia, and Strongyloides
stercoralis [5661]. Opportunistic malignancies, such as
Kaposi sarcoma [62] and Epstein-Barr virus (EBV)associated lymphoma have been reported in patients
with ATL [63]. Although in the last 20 years considerable progress has been made regarding the biology of

Concise Review: Current Views in HTLV-I-Associated Adult T-Cell Leukemia/Lymphoma

HTLV-I, treatment of ATL patients remains unsatisfactory. ATL generally has a very poor prognosis and,
in leukemic or lymphomatous presentation, life expectancy does not exceed 1 year. High-dose radiotherapy
or chemotherapy regimens, by themselves or in combination, including those designed for the treatment of
aggressive non-Hodgkin lymphomas or acute lymphoblastic leukemia, are ineffective in ATL patients.
Although initial treatments often result in complete
remissions (40% CR), all patients relapse and die,
usually in less than a year. The poor prognosis of
ATL results from a combination of several factors.
Immune deficiency often results in opportunistic infections, and failure of hepatic functions prevents administration of intensive induction treatments. Other
negative factors include the intrinsic resistance of
ATL cells to apoptotic stimuli, often facilitated by
mutations in the p53 gene [64] and p16ink [65], overexpression of multidrug resistance [66], and the ATLderived factor (ADF), a thioredoxin analogue [67,68].
Many polychemotherapy clinical trials were carried out
in Japan between 1978 and 1983 [69], and although the
CR rate was usually higher in the lymphoma type as
compared to acute ATL, the long-term survival was
identical. Despite these obstacles recent encouraging
results were obtained by allogeneic bone marrow transplantation (alloBMT) [70], combinations of AZT and
a-IFN [7174], arsenic trioxide and a-IFN [75,76], alltrans-retinoic acid (ATRA) therapy [7779], and the
use of radiolabeled anti IL-2R (CD25) antibodies
[80,81]. Current therapeutic strategies for the treatment
of ATLL have recently been reviewed [82].
Molecular Pathogenesis

The low incidence and the long latency of HTLV-Iassociated ATLL suggest, in addition to viral infection, accumulations of genetic mutations are required
for cellular transformation in vivo. HTLV-I-mediated
T-cell transformation presumably arises from a multistep oncogenic process [83], in which the virus or
environmental factors induce chronic T-cell proliferation resulting in an accumulation of genetic defects
and the deregulated growth of infected cells. There is
a recognized discrepancy between the number of cells
carrying the provirus and the expression of viral
mRNA, even in the early stages of the disease [84].
Two possible models may explain this observation:
either cells are latently infected or cells expressing
viral antigens are rapidly eliminated by immune
responses. The higher viral load and polyclonal expansion of infected cells observed in TSP/HAM pathogenesis, suggest it may result from chronic virus
expression and a state of balance with the immune
system. However, to achieve the monoclonal expansion

235

that characterizes ATL [85], the virus has to establish a

latent reservoir that can be amplified by cellular replication. In fact, studies of clonal expansion of HTLVI-infected cells in HTLV-I carriers, demonstrate some
clones persist for over 7 years in the same individual
[86,87]. We have recently found that the virally encoded
p30 protein prevents nuclear export of the tax/rex
RNA and suppresses viral gene expression in vitro
[88]. Whether or not p30 may act as latency factor in
vivo remains to be investigated.
While it is not yet fully understood how HTLV-I
engenders ATLL, several lines of evidence have established that the viral oncoprotein Tax plays a central
role, at least in the early stages of the disease [89]. Tax
usurps signaling pathways, including NF-kappa B
[90], leading to the up-regulation of numerous cytokines and cytokine receptors. Remarkably, Tax has
been shown to up-regulate expression of IL-2 and
IL-2Ra chain [91,92] as well as IL-15 and IL-15Ra
chain [93,94], suggesting that an autocrine/paracrine
mechanism could be involved in proliferation of
ATL cells in early stages of infection [95]. Of note,
recent studies have found that the viral protein p12
stimulates production of IL-2 in activated T-cells [96],
interacts with the IL-2 receptor b chain, and stimulates the Jak/STAT5 pathway and T-cell proliferation
[97]. A more detailed role of p12 in HTLV-I pathogenesis has recently been reviewed [98]. A common
and striking feature of ATL cells in late stages of the
disease is the absence of detectable Tax expression,
suggesting that Tax expression may no longer be
required [99]. However, ATL cells appear to have
acquired a Tax phenotype: NF-kB and AP-1 are
constitutively activated [100,101], p53 is stabilized
and functionally impaired in the absence of mutations
[102], and expression of p21waf, survivin, and Bcl-xL
is increased [103106].
During the transformation process, Tax is also
involved in deregulation of cell growth [107] and apoptosis pathways [108,109], repression of the b-polymerase [110], the host DNA repair machinery [111], the
anaphase promoting complex [112], and inactivation
of the mitotic arrest defective (MAD1) protein [113].
These effects increase the occurrence and accumulation
of somatic mutations and predispose HTLV-I infected
cells to chromosome instability. As expected, reactivation of the human telomerase gene catalytic subunit
(hTERT) and increased telomerase activity is commonly found in HTLV-I infected cell lines in vitro
and in ex vivo ATL cells [114118]. Recent studies
demonstrate Tax, through its NF-kB inducing activity,
stimulates hTERT expression in HTLV-I-infected cells,
allowing maintenance of long telomeres and avoidance
of replicative senescence [118]. However, in the
presence of antigenic stimulation of T-lymphocytes

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Concise Review: Nicot

bearing Tax, hTERT mRNA induction is diminished

[118,119]. hTERT is highly inducible in lymphocytes
following activation through CD3, possibly to maintain genetic stability of actively dividing cells. We propose the following model: in HTLV-I-infected T-cells,
Tax-mediated down-regulation of Lck, TCR, CD45,
and Syk/Zap-70 kinase expression results in attenuations of CD3 responses [120,121] and prevents the
full induction of hTERT expression following TCR
engagement. In turn, active cellular proliferation in
the presence of limiting amounts of telomerase may
result in a transient state of genetic instability. Once
the mitogenic effect has vanished, Tax-mediated activation of hTERT may stabilize and, thereafter, promote
the long-term expansion of potential tumor cells
that have acquired chromosomal abnormalities. Several cycles of transient active proliferation combined
with chromosomal instability may be required for a
clonal selection and the development of adult T-cell
leukemia. In support of such a model, a high frequency
of T-cell clonal expansion has been associated
with chronic antigenic stimulation in carriers of
S. stercoralis [122,123], and a higher frequency of leukemia has been reported in individuals carrying this
parasite [124126].
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